Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors

Purpose: A single-agent dose-escalating phase I and pharmacokinetic study o n the farnesyl transferase inhibitor SCH 66336 was performed to determine t he safety profile, maximum-tolerated dose, and recommended dose for phase I I studies. Plasma and urine pharmacokinetics were determined. Patients and Methods: SCH 66336 was given orally bid without interruption t o patients with histologically or cytologically confirmed solid tumors. Rou tine antiemetics were not prescribed. Results: Twenty-four patients were enrolled onto the study. Dose levels stu died were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacakinetic sampling w as performed on days 1 and 15. At 400 mg kid, the dose-limiting toxicity (D LT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia , and the combination of grade 3 anorexia and diarrhea with reversible grad e 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the D LTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and t he combination of grade 3 fatigue with grade 2 nausea and diarrhea. The rec ommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater th an dose-proportional increase in drug exposure and peak plasma concentratio ns, with increased parameters at day IS compared with day 1, indicating som e accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hou rs and seemed to increase with increasing doses. Steady-state plasma concen trations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compar tment. Conclusion: SCH 66336 can be administered safely using a continuous oral bi d dosing regimen. The recommended dose for phase II studies using this regi men is 200 mg bid.